The long-term goal of these studies is to attain a more fundamental understanding of the functions of NMDA receptors in development, in the mature brain, and in neurological diseases. To this end we have designed complementary experiments with the Xenopus oocyte expression system and the hippocampal slice preparation to answer the following questions: Is the sensitivity of the NMDA receptor to glycine, Mg or MK-801 regulated at the transcription level during development or in different brain regions? Are NMDA and quisqualate/kainate receptors encoded by different size transcript ? Do multiple transcript size classes encode NMDA receptors? What structural features of ligands promote agonist, antagonist and partial agonist activit at the glycine site? What functions does the glycine site subserve in synaptic transmission mediated by NMDA receptors in the hippocampal slice? Does the ionic permeability of NMDA receptors expressed in oocytes differ from that of receptors in their native neuronal environment? Can NMDA receptor mRNA be identified in Northern blots with an oligonucleotide probe shown in our laboratory to arrest the translation of NMDA but not kainate receptors? Can this oligonucleotide (or other similar ones) be used to scre n existing cDNA libraries to identify subunits of the NMDA receptor? A combination of molecular biological and electrophysiological techniques wil be used to address these questions.